Chapter 2 Botulinum neurotoxin: history of clinical development
The clinical development of botulinum neurotoxin began in the late 1960s with the search for an alternative to surgical realignment of strabismus. At that time, surgery of the extraocular muscles was the primary treatment for strabismus, but it was unsatisfactory for some patients because of the variability in results, consequent high reoperation rates and its invasive nature. In an attempt to find an alternative, Alan B. Scott, an ophthalmologist from the Smith–Kettlewell Eye Research Institute in San Francisco, investigated the effects of different compounds injected locally into the extraocular muscles to chemically weaken them. The drugs tested initially proved unreliable, short acting or necrotizing (Scott et al., 1973).
About this time, Scott became aware of Daniel Drachman, a renowned neuroscientist at Johns Hopkins University and his work, in which he had been injecting minute amounts of botulinum neurotoxin directly into the hind limbs of chickens to achieve local denervation (Drachman, 1964). Drachman introduced Scott to Edward Schantz (1908–2005), who was producing purified botulinum neurotoxins for experimental use and generously making them available to the academic community. Schantz himself credits Vernon Brooks with the idea that botulinum neurotoxin might be used for weakening muscle (Schantz, 1994). Brooks worked on the mechanism of action of botulinum toxin for his PhD under the mentorship of Arnold Burgen, who suggested the project to him (Brooks, 2001). Schantz had left the US Army Chemical Corps at Fort Detrick, Maryland, in 1972 to work at the Department of Microbiology and Toxicology, University of Wisconsin in Madison. Using acid precipitation purification techniques worked out at Fort Detrick by Lamanna and Duff, Schantz was able to make purified botulinum toxins.
In extensive animal experiments, low doses of botulinum neurotoxin produced the desired long-lasting, localized, dose-dependent muscle weakening, reportedly without any systemic toxicity and without any necrotizing side effects (Scott et al., 1973). Based on these results, the US Food and Drug Administration (FDA) permitted Scott in 1977 to test botulinum neurotoxin in humans under an Investigational New Drug (IND) license for the treatment of strabismus. These tests proved successful and the results of 67 injections were published in 1980 (Scott, 1980). With this publication, botulinum neurotoxin was established as a novel therapeutic. Scott approached several drug companies to take the drug on and manufacture it. However, he had disclosed the drug in earlier publications and thus could not get it patented. Without this, none of the manufacturers would undertake it. Scott then moved the activity from Smith–Kettlewell, setting up his own company, Oculinum, in Berkeley California. Dennis Honeychurch, a pharmacist, joined him and devised many of the tests for safety, potency, stability, sterility and water retention in the freeze-dried product that were required before botulinum toxin could be registered as a drug by the FDA. In addition to establishing a laboratory for testing and record keeping, a sterile facility for filling and freeze-drying was required. This was found at Adria Labs in Albuquerque, where Scott and Honeychurch went several times a year to fill 8000–10 000 vials.
Sometime in the 1960s, Robert Crone, Professor of Ophthalmology in Amsterdam, whose interest was in strabismus, was able to get the Porton group to send him dried toxin from the UK, with the idea of strabismus use. The package was damaged, and dried toxin leaked out – probably enough to kill all Amsterdam (A. Scott, personal communication)! Crone decided not to pursue it further. By the early 1980s, Scott and colleagues had injected botulinum neurotoxin for the treatment of strabismus, blepharospasm, hemifacial spasm, cervical dystonia and thigh adductor spasm (Scott, 1994). Prior to FDA approval, the neurotoxin was made available to a group of investigators for research, including Colne, Dykstra, Fahn, Hallet, Jankovic and Roggenkamper. Stanley Fahn’s group at Columbia University reported in 1985 the first double-blind study testing Scott’s toxin in improving the symptoms of blepharospasm (Fahn et al., 1985). Also in 1985, Tsui and colleagues reported the successful use of botulinum neurotoxin for the treatment of cervical dystonia in 12 patients based on the earlier dosage data from Scott’s injections (Tsui et al., 1985). This was followed by the first double-blind, crossover study in which botulinum neurotoxin was found to be significantly superior to placebo at reducing the symptoms of cervical dystonia, including pain (Tsui et al., 1986). The therapeutic use of botulinum neurotoxin for the treatment of blepharospasm and hemifacial spasm proceeded along similar lines, with several groups reporting success for these indications by the mid 1980s and documenting the benefits of repeated injections after the effects waned (Frueh et al., 1984; Mauriello, 1985; Scott et al., 1985). Brin et al. (1987) reported on use of Scott’s toxin to treat multiple dystonias (e.g. cranial, cervical, laryngeal, limb) and related hyperkinetic disorders. Reports of the successful use of botulinum neurotoxin in many conditions of focal muscle overactivity continued, including spasmodic dysphonia (Blitzer et al., 1986; Truong et al., 1991), oromandibular dystonia (Jankovic and Orman, 1987), dystonias of the hand (Cohen et al., 1989) and limb spasticity (Das and Park, 1989). Soon, botulinum neurotoxin was accepted as safe and efficacious for blepharospasm, cervical dystonia and other focal dystonias, and was the treatment of choice for some indications (National Institutes of Health, 1991).
In December 1989, the FDA licensed the manufacturing facilities and batch 79–11 of botulinum neurotoxin type A was manufactured by Scott and Schantz in November 1979. The therapeutic preparation contained 100 mouse units of neurotoxin per vial. A mouse unit was defined as the LD50 for Swiss Webster mice. Scott named this drug Oculinum (ocu and lining-up) and it was recognized as an orphan drug for the treatment of strabismus, hemifacial spasm and blepharospasm. According to Scott (personal communication), he asked FDA to approve 88–4, a four times more potent batch for which he had ample data. However, the FDA required the use of 79–11 in the USA because it was used for generating most of the clinical data on which approval was based. Some European regulatory agencies accepted 88–4 with the initial filings. All current neurotoxins have greater specific potency than 79–11 and are equal to or better than 88–4. For about 2 years, Scott’s Oculinum Inc. was the licensed manufacturer, with Allergan Inc. (Irvine, CA, USA) the sole distributor. Manufacturing rights and license were acquired by Allergan in late 1991; a different batch of Botox was distributed in 1998. This and subsequent batches of Botox contained less protein per mouse unit, which may have made them less liable to elicit antibodies than the original batch 79–11.
The name Botox was perhaps first used by Stanley Fahn and Mitchell Brin, who did not think of it as a possible trade name. Around 1985, Scott trademarked the name B-botox for the type B neurotoxin that he studied. Finding type B was inferior to type A, he abandoned it and also the name. “Botox” is a name readily derived from the laboratory lingo for toxins, probably newly invented several times prior to Allergan’s use (A. Scott, personal communication). The non-proprietary name is now onabotulinumtoxinA.
In 2000, a product containing the botulinum neurotoxin B serotype, NeuroBloc/MyoBloc, was registered with the FDA by Elan Pharmaceuticals (South San Francisco, CA, USA) with the indication of cervical dystonia. MyoBloc is the trade name in the USA and NeuroBloc is the trade name used elsewhere. The name NeuroBloc was coined by Mitchel Brin and MyoBloc by Lloyd Glenn (Elan). The initial research on botulinum toxin B was carried out by Tsui, Truong and O’Brian. MyoBloc was eventually sold to Solstice Neurosciences Inc. (Malvern, PA, USA) and recently to US WorldMeds (Louisville, KY, USA). The generic name is rimabotulinumtoxinB. Botox was also approved for cervical dystonia in 2000.
In Europe, botulinum neurotoxin was first produced for therapeutic purposes at the Defence Science and Technology Laboratory in Porton Down, UK. When the product was commercialized, the manufacturing operations were renamed several times – to Centre of Applied Microbiology and Research (CAMR), Porton Products, Public Health Laboratory Service (PHLS) and Speywood Pharmaceuticals. In 1994, Speywood Pharmaceuticals was acquired by Ipsen (Paris, France). The UK botulinum neurotoxin product was first registered in 1991 as Dysport (dystonia Porton Products; non-proprietary name now abobotulinumtoxinA). It is now manufactured for worldwide use by Ipsen (Slough, UK). It was approved in the USA for cervical dystonia and glabellar facial wrinkles in April 2009. It was first used to treat strabismus and blepharospasm in the UK not long after Scott’s initial reports (Elston 1985; Elston et al., 1985). The movement disorders group of C. David Marsden at the National Hospital of Neurology and Neurosurgery, London pioneered its use in neurology (Stell et al., 1988). Soon afterwards, Dirk Dressler, a student of Marsden, introduced this product (Dysport) to continental European neurology (Dressler et al., 1989). However, it was Roggenkamper who personally carried botulinum neurotoxin (Oculinum) that he received from Alan Scott to Germany and who initiated investigations in patients with blepharospasm (Roggenkamper, 1986). A flabbergasted German custom officer waved Roggenkamper with his hand-carried botulinum neurotoxin into Germany without even looking as he perceived Roggenkamper’s declaration as a joke (Roggenkamper, personal communication). More details about the expansion of botulinum neurotoxin therapy in continental European are described by Homann et al. (2002).
Subsequently, another botulinum neurotoxin drug named Xeomin (incobotulinumtoxinA) was marketed by Merz Pharmaceuticals (Frankfurt/M, Germany). It is a botulinum neurotoxin type A preparation with high specific biological activity and, as a consequence, a reduced protein load (Dressler and Benecke, 2006). Structurally, it is free of the complexing botulinum neurotoxin proteins. It is currently approved in most European countries, USA, Canada, some middle and South American countries, as well as several Asian countries. Besides blepharospasm, cervical dystonia and glabellar lines, it is also approved for spasticity and some other indications depending on the country.
An additional source of therapeutic botulinum neurotoxin type A is the Lanzhou Institute of Biological Products (Lanzhou, Gansu Province, China), where the manufacturing expertise comes from Wang Yinchun, a former collaborator of Schantz. Wang used the protocol for acid precipitation of the crystalline toxin from the cultures worked out at the Army Chemical Laboratories at Fort Detrick (A. Scott, personal communication). Its product was registered as Hengli in China in 1993. In some other Asian and South American markets, it is distributed as CBTX-A, Redux or Prosigne. The international marketing is provided by Hugh Source International Ltd (Kowloon, Hong Kong). Registration of this product in the USA and in Europe seems unlikely. Publications about this product are scarce.
In South Korea and some other Asian countries, Neuronox, a botulinum neurotoxin type A drug manufactured by Medy-Tox (Ochang, South Korea), is distributed. Other botulinum neurotoxin drugs are under development at Tokushima University, Tokushima City, Japan and at the Mentor Corporation (Santa Barbara, CA, USA).
Over the years that these other products were developed, the clinical applications for botulinum neurotoxin continued to expand. Botox, which has most indications, was further approved by the FDA for glabellar rhytides in 2002 and for primary axillary hyperhidrosis in 2004. In 2010, Botox was approved for chronic migraine and upper limb spasticity in adults, in 2011 for the treatment of neurogenic detrusor overactivity and in 2013 for overactive bladder. Off-label use by physicians is widespread and includes tremor, anal fissure, achalasia, various conditions of pain and others (Dressler, 2000; Moore and Naumann, 2003; Truong and Jost, 2006). Outside the USA, there are at least 20 indications in 83 countries. Numerous formal therapeutic trials for registration are in progress. The use of Botox for wrinkles has been very popular and is perhaps the indication best known by general public.
These expanded uses were paralleled by increased understanding of the mechanism of action of botulinum neurotoxins from basic research (Lalli et al., 2003). The multistep mechanism of action postulated by Simpson (1979) was verified, and research on botulinum neurotoxin has itself contributed much to the understanding of vesicular neurotransmitter release. It has also been demonstrated that botulinum neurotoxin, which was once believed to exert its activity solely on cholinergic neurons, can, under certain conditions, inhibit the evoked release of several other neurotransmitters (Welch et al., 2000; Durham et al., 2004). These discoveries continue to intrigue basic scientists and clinicians alike, as the therapeutic uses and applications of botulinum neurotoxin appear destined to increase still further in the years to come.
